Therapeutic composition



United States Patent THERAPEUTIC COMPOSITION Robert E. Allen, Wyoming,and Frank P. Palopoli and Edward L. Schumann, Cincinnati, Ohio, andMarcus G. Van Campen, .Jr., Berkeley, Calif., assignors to The -Wm. S.Merrell Company No Drawing. Application August 6, 1957 I 7 Serial N0.676,479

'3 Claims. (Cl. 260-570) As estrogen antagonists, the compounds areuseful in I the treatment of hyperestrogenism and disorders relatedtothis condition, .e.g., endometriosis, Kleinfelters syndrome,dysmenorrhea, menopausal dysfunction, functional bleeding and similarconditions. They are active both orally and parenterally and so can beadministered by either route, though the oral route is preferred in mostinstances. Some ofthe compounds have a high degree of activity asestrogen antagonists and are also advantageous'ly nonestrogenic. Some ofthe compounds with anti-estrogenic activity are also uterotrophic.

As anti-inflammatory agents, the compounds are useful in alleviating thesymptoms of such collagen diseases as arthritis and rheumatism and inthe topical treatment of inflammation. Some of the compounds possess thenovel combination of anti-inflammatory and anti-estrogenic activitiesand are especially advantageous for this reason.

-As blood cholesterol depressants, the compounds are useful in thetreatment of atherosclerosis.

1 As gonadotrophic inhibition agents, the compounds are useful for thetreatment of fertility and sterility problems and can be administeredorally or parenterally for this purpose.

The compounds can be used orally and parenterally in doses rangingbetween mg. and 2 to 4 grams daily, depending on the condition undertreatment. For topical use, the compounds can be incorporated intocreams, ointments or lotions in concentrations of up to 10 percent. Inaerosol sprays, the concentration can be in the order of about 0.05 to 1percent.

The compounds can be isolated and are generally useful in the form oftheir salts with mineral acids'such as hydrochloric or hydrobromic acidor with organic acids such as citric, oxalic or the like. They can beused as the base, however.

The compounds of our invention are derivatives of triphenylethylenes inwhich one of the phenyl groups is substituted by a basic ether group ofthe formula described below and in which the mono-phenyl substitutedcarbon atom in the ethylene group is linked to halogen. The newcompounds have the formula Q X a R -Q in which one of the groupsrepresented by R is a basic ether group of the formula OC,,H ,,A,wherein -n is 2, 3 or 4 and A is a dialkylamino group in which the alkylgroup contains from 1 to 4 carbon atoms, or a cyclic structure such as aN-piperidyl, or a N-morpholinyl group. The group OC,,H ,,A is attachedto the benzene ring by the oxygen atom in the para position to the pointof attachment of the benzene ring to the ethylene group. The benzenenucleus substituted with the OC,,H ,,A group must be attached to acarbon atom bearing a second benzene nucleus. The remaining R group andthe R group are hydrogen, halogen or methoxy and X is halogen.

The new haloethylenes can be generally prepared by halogenation of thecorresponding ethylenes of the forrnula wherein and R and R substituentshave the same meaningxdescribed above. These ethylenes are described inour pending applications Serial No. 620,570, filed November 6, 1956, nowabandoned and Serial No. 682,073, filed September 5, 1957.

The haloethylenes are prepared by the halogenation of the ethylenesusing bromine, chlorine or N-chloroor N-bromosuccinimide. They can alsobe prepared by halogenation of the hydrochloride or hydrobromide salt ofthe ethylenes with N-chloroor N-bromosuccinimide, respectively. They canalso be prepared by treatment of the corresponding ethanols withbromine.

The ethylene starting materials can be generally prepared by dehydrationof the corresponding ethanols of 'the'formula1-[p-(B-dimethylaminoethoxy)phenyl] 1 phenyl-Z-panisylchloroethylene.-Amixture of 25 g. of the hydrochloride of 1 [p (fldimethylaminoethoxy)phenyl]-lphenyl-Z-p-anisylethylene and 9.4 g. ofN-chlorosuccinimide in 300 cc. dry chloroform was refluxed 18 hours. Thesolution was Washed with an excess of 5 percent sodium hydroxidesolution, dried over anhydrous potassium carbonate, and the solvent wasreplaced with butanone. A solution of 12 g. of citric acid in butanonewas added and the dihydrogen citrate salt of 1-[p-(,B-dirnethylaminoethoxy)phenyl] 1 phenyl-2-p-anisylchloroethylene wasobtained, melting at -102" C.

This compound exhibits estrogenic estrogen antagonist andanti-inflammatory activities and activity in decreasing bloodcholesterol levels.

Example 2 1-[p-(B-dimethylaminoethoxy)phenyl] lphenyl-2-panisylbr0moethylene.-To a solution of 50 g. of l-[p-(B-dimethylaminoethoxy)phenyl] l phenyl-Z-p-anisyletha- 1101 in 250 cc.glacial acetic acid was slowly added with stirring a, solution .of 40 g.of bromine in 25 0 .cc. of acetic acid. After the mixture was stirred atroom tempera ture for an hour, excess 10 percent sodium hydroxide wasadded and an ether extract was washed with water and dried. The etherwas replaced with butanone and a solution of 32.6 g. of citric acid inethanol was added. After repeated recrystallizations of the product frombutanone, the dihydrogen citrate salt ofl-lfp-(fl-dimethylaminoethoxy)-phenyl]-1-phenyl-2-p anisylbromoethylenewas obtained, melting at 114l16 C.

This compound exhibits gonadotrophic inhibitory activity.

Example 3 1-[p-(B-diethylaminoethoxy)phenyl]-1,2-diphenylchl0-rethylene.-A mixture of 20 g. of l-[p-(B-diethylaminoethoxy)phenyl]-1,2-diphenylethanol in 200 cc. of ethanol containing an excessof hydrogen chloride was refluxed 3 hours. The solvent and excesshydrogen chloride were removed under vacuum, and the residue wasdissolved in a mixture of ethyl acetate and methylene chloride.1-[p-(fl-diethylaminoethoxy)phenyll 1,2 diphenylethylene hydrochloridewas obtained, melting at 148-157 C. This hydrochloride salt was treatedwith N-chlorosuccinimide as in the procedure of Example 1. The productthen obtained was converted to the free base and treated with citricacid. The dihydrogen citrate salt of l-[p-(fidiethylaminoethoxy)phenyl]-1,2 diphenylchloroethylene was obtained, melting at 116.5-118 C.

The intermediate 1-[p-(B-diethylaminoethoxy)phenyll- 1,2diphenylethanolwas obtained by treating 4-(13-diethylaminoethoxy)benzophenone withbenzylmagnesium chloride. It melted at 95-96 C.

This compound exhibits uterotrophic estrogenantagonist, gonadotrophicinhibitory and anti-inflammatory activities and activity in decreasingblood cholesterol levels.

Example 4 1-[p (5 dietlzylaminoethoxy)phenyl] 1phenyl-Z-panisylclzIor0ethylene.-Twenty grams ofI-[p-(B-diethylaminoethoxy)phenyll-1-phenyl-2-p-anisylethanol wasdehydrated as in Example 3. The solvent was evaporated and the crudehydrochloride salt was dissolved in chloroform and treated withN-chlorosuccinimide as in Example 1. The free base was isolated, treatedwith 9.6 g. of citric acid and the dihydrogen citrate salt ofl-lp-(B-diethyl- .aminoethoxy)phenyl]-1-phenyl-2-p anisylchloroethylenewas obtained, melting with decomposition at 127 C.

This compound exhibits weakly esterogenic estrogen antagonist,gonadotrophic inhibitory and anti-inflammatory activities and activityin decreasing blood cholesterol levels.

Example 6 1- [p- (,8-diethylamin0ethoxy )phenyll -1-phenyI-2-p-chl0-rophenylchl0r0ethylene.-To a solution of 20 g. of the hydrochloride saltof l-[p-(fl-diethylaminoethoxy)-phenyl]-1-phenyl-Z-p-chlorophenylethylene in 200 cc. of dry chloroformwas added slowly with stirring'a solution of 4.3 g. of chlorine in 90cc. of carbon tetrachloride over a period of an hour. The mixture wasshaken with excess 10 percent sodium hydroxide solution and dried overanhydrous potassium carbonate. The solvent was removed and replaced withbutanone, and a molecular equivalent of citric acid in butanone wasadded. The dihydrogen citrate salt of 1-[p-(fi-diethylaminoethoxy)-phenyl]-l-phenyl-2-p-chlorophenylchloroethylene was obtained, melting at111-1 12 C.

This compound exhibits weakly estrogenic estrogen antagonist,gonadotrophic inhibitory and anti-inflammatory activities.

Example 7 1-[p-(fi-dibutylaminoelhoxy)phenyl] -1-pher1yl Z-p-amisylchl0r0etkylene.Following the procedure of Example 7, using 14 g. ofl-[p-(B-dibutylaminoethoxy)phenyl]- l-phenyl-2-p-anisylethanol, therewas obtained the hydrochloride salt of1-[-p-(fi-dibutylaminoethoxy)phenyll-lphenyl-Z-p-anisylchloroethylene,melting at 149-153 C.

This compound exhibits uterotrophic estrogen antagonist, gonadotrophicinhibitory and anti-inflammatory activities.

Example 9 1-[p-(ql-diethylaminopropoxy)phenyl] 1,2diphenylchl0r0ethylene.-A mixture of 113 g. of the sodium salt of4-hydroxybenzophenone and an excess of 'y-dicthylaminopropyl chloride in300 ml. of dry toluene was refluxed 20 hours, the mixture was washedwith 10 percent sodium hydroxide solution, then water and distilled.4-('y-diethylaminopropoxy)benzophenone was obtained, boiling at 220 C.at 0.6 mm., n =1.5680. A solution of g. of this ketone in 200 ml. of drybenzene was treated with 600 ml. of an ethereal solution containing 0.33mole of benzylmagnesium chloride. After decom posing the mixture withammonium chloride solution, the dihydrogen citrate salt was formed ofthe product, l-lip-('y-diethylaminopropoxy)phenyl] -1,2 diphenylethanol,melting at 121 C. This ethanol, converted to the free base by treatmentwith 10 percent sodium hydroxide solution, was dehydrated andchlorinated according to the procedure of Example 7 to give thehydrochloride salt ofl-lp-('y-diethylaminopropoxy)phenyl]-1,2-diphenylchloroethylene, meltingat 112 C.

Example 10 1- [p- (fl-piperidinoethoxy)phenyl] -1-phenyl-2p-anisylchloroethylene.-Following the procedure of Example 7, using 26g. of 1-[p-(p-piperidinoethoxy)phenyl]-1-pheny1-2-p-anisylethanol, therewas obtainedl-[p-(fl-piperidinoethoxy)phenyl]-1-phenyl-2-p-anisylchloroethylenehydrochloride, melting at 186187 C.

This compound exhibits Weakly estrogenic estrogen antagonist,gonadotrophic inhibitory and anti-inflammatory activities.

Example 11 l [p-(fi-morpholinoethoxy) phenyl] -1,2-dz'phenyZchl0r0-ethylene.When 1-[p-(fi-morpholinoethoxy)phenyll-1,2- diphenylethylenehydrochloride was treated with an equivalent of N-chlorosuccinimide inchloroform, 1- [p-(flmorpholinoethoxy)phenyll 1,2 diphenylchloroethylenewas obtained, whose hydrochloride salt melted at 203 C.

The '1-[p-(j8-morpho1inoethoxy)phenyl]-1,2-diphenylethylene was obtainedas follows: 4-(B-morpholinoethoxy)benzophenone was prepared by refluxing16 hours a mixture of 100 g. of 4-hydroxybenzophenone and29 g. of sodiummethoxide in 400 ml. of ethanol with a solution ofN-B-chloroethylmorpholine (prepared from 100 g. of the hydrochloridesalt) in 200 ml. of benzene. The solvents and precipitated sodiumchloridewere removed, the residue was taken up in ether, washed with '10percent sodium hydroxide, then water and dried over magnesium sulfate.While removing ether, the 4-(fl-morpholinoethoxy)benzophenone separated,giving 121 g., melting at 8384 C.

Analysis.Calcd. for C H NO C, 73.28; H, 6.80; N, 4.50. Found: C, 73.03;H, 7.19; N, 4.76.

The Gn'gnard of 26 g. of benzyl chloride in 250 ml. of dry ether wasadded to 51 g. of 4-(fi-morpholinoethoxy)-benzophenone in 100 ml. of drybenzene, and after an hour of stirring was decomposed with percentammonium chloride solution. The organic layer was dried over anhydrousmagnesium sulfate, the solvent was replaced with ether whereuponI-[p-(B-morpholinoethoxy)phenyl]-l,2-diphenylethanol separated, meltingat 113114 C.

Analysis.-Calcd. for C H NO C, 77.40; H, 7.25; N, 3.47. Found: C, 77.11;H, 7.28; N, 3.67.

A solution of 31 g. of l-[p-(B-morpholinoethoxy)-phenyl]-1,2-diphenylethanol in 200 ml. of alcohol containing an excessof anhydrous hydrogen chloride was refluxed for an hour. The solvent andexcess hydrogen chloride were removed under vacuum and the residue wasdissolved in hot ethyl acetate containing a little methanol. Crystals ofthe hydrochloride salt of l-[p-(B-morpholinoethoxy)phenyl]-l,2-diphenylethylene were obtained which meltedat 151181 C.

Analysis.Calcd. for C H NO HCl: C, 74.00; H, 6.69; N, 3.32. Found: C,73.92; H, 6.50; N, 3.31.

All of the compounds of the above examples exhibited the activitiesdescribed for each when administered parenterally (subcutaneously).Also, the compound of Example 3 exhibited anti-inflammatory activitywhen administered orally.

The following examples illustrate suitable pharmaceutical compositionscontaining the new compounds. In these examples, the quantities aregiven for single units, it being understood that in actual practice, thedosage forms will be prepared in suitable quantities, and the amounts ofthe materials adjusted accordingly.

Example 12 25 mg. tablezs.-Twenty-five mg. of the citrate of 1-[p-(B-diethylaminoethoxy)phenyl] -1-p-phenyl- 2 p-anisylchloroethylene(Example 5), 48 mg. of powdered sugar, and 32 mg. of corn starch aremixed and granulated with 10 percent gelatin solution. The granulationis dried and ground to fine granules for tableting. About 1 percentmagnesium stearate is added as a lubricant, together with sufficientcorn starch to give a weight of 2.5 grains per tablet. The product iscompressed on a single punch or rotary machine using a inch punch.

Example 13 500 mg. tablers.-Five hundred mg. of the citrate of 1- [p-(,B-diethylaminoethoxy) phenyl] -1-phenyl-2-(p-chlorophenyl)chloroethylene (Example 6) in finely powdered form isadmixed with 60 mg. of corn starch and 100 mg. of powdered sugar andthen granulated with 10 percent gelatin solution. The granulation isdried and ground to size suitable for tableting. About 1 percentmagnesium stearate is added as a lubricant, together with sufficientcorn starch to give a weight of 700 mg. per tablet. The product iscompressed on a single punch or rotary machine using a A inch punch.

The tablets of Example 12 and Example 13 may be suitably coated ifdesired, as, for example, with sugar.

Example '14 I Capsule- Iwenty-five mg. of the citrate .ofLip-(fldiethylaminoethoxy)phenyl] 1- phenyl 2 p anisylchloroethylene(Example 5) is admixed withcorn starch .in quantity required to providesuflicient bulkfor the desired size capsule, and the mixture isencapsulated.

' Example 15 Capsule.Five hundred mg. of,the citrate of'l-Ip-(fldiethylaminoethoxy)phenyl] 1 phenyl -.2 (p chlorophenyl)chloroethylene (Example 6) is admixed with sufiicient corn starch togive the proper bulk for the desired size capsule, and the mixture isencapsulated.

7 Example 16 Injectable suspension, 100 mg. per ml.-The followingingredients are sterilized separately: 100 mg. ofthe hydrochloride of1-[p-(B-di-n-butylaminoethoxy)phenyl]-1-phenyl-2-p-anis1ychloroethylene(Example 8), 0.1 mg. of Tween and q.s. corn oil to make a final volumeof one ml. These ingredients are admixed aseptically. Particle size maybe achieved by use of mioronized material or by use of a ball mill,maintaining aseptic conditions. The above suspension may be administeredsubcutaneously and intramuscularly.

Example 17 Oral suspension, 700 mg. per 15 ml.-One hundred fifty mg. ofmagnesium aluminum silicate are hydrated in about 9 ml. of water; 500mg. of sorbitan monooleate, 700 mg. of the citrate of1-[p-(B-diethylaminoethoxy)- phenyl] 1 phenyl 2 anisylchloroethylene(Example 5), color and flavor, as desired, and Water q.s. 15 ml. areadded; the product is mixed well and homogenized.

Example 18 Liquid (syrup) 25 mg. per teasp00n.--Twenty-five mg. of thecitrate of 1-[p-(B-diethylaminoethoxy)phenyl]-1-phenyl-2-anisylchloroethylene (Example 5) is dissolved in one ml. ofwater. Five mg. of sodium benzoate, 3.5 ml. of liquid sugar, 5 mg. ofcitric acid, and 0.375 mg. of butoben are added and stirred untildissolved, using gentle heat it necessary. Flavor, as desired, and waterq.s. are then added.

Example 19 Liquid (syrup) 500 mg. per tablespoon-Five hundred mg. of thecitrate of 1- [p-(p-diethylaminoethoxy)- phenyl] 1 phenyl 2 panisylchloroethylene (Example 5) and 4.5 mg. of sugar are dissolved insuflicient water so that after the addition of 2.25 ml. of alcohol USPand flavor, as desired, the volume is 15 ml.

Example 20 Injectable solution, 2 mg. per mL-Two mg. of thehydrochloride of 1 [p (e di n butylaminoethoxy)-phenyl]-1-phenyl-2-paanisylchloroethylene (Example 8) and water forinjection q.s. one ml. are mixed and warmed I 7 wherein only one of thegroups represented by R is a group of the formula OC,,H ,,A, attached bythe oxygeri atom to thehenzene ring in para position to the pointofattachment of the benzene ring to the carbon atom of the straight chaingroup, wherein n is an integer of 2 to 4 5 and A is selected from thegroup consisting of dialkylhalogen and methoxy, and X is halogen.

8 2. -1 7 [p (,3 diethy1aminoethoxy)phenyl] 1,2 diphenylchloroethylene.

3. 1 [p (5 diethylaminoethoxy)phenyl] lphenyl-Z-p-anisylchloroethy1ene.

References Cited in the file of this patent UNITED STATES PATENTS2,703,324 Binkley et a1. Mar. 1, 1955

1. COMPOUNDS OF THE FORMULA